Novel KRAS inhibitor adagrasib findings reported for advanced NSCLC
medwireNews: Adagrasib could play a role in the treatment of advanced non-small-cell lung cancer (NSCLC) with a KRAS G12C mutation, indicates early research presented at the European Lung Cancer Virtual Congress 2021.
Gregory Riely (Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA) reported findings for the novel oral selective KRAS inhibitor in a cohort of 79 patients participating in the KRYSTAL-1 trial, all of whom had unresectable or metastatic KRAS G12C -positive NSCLC that had previously progressed on or after PD-L1 inhibitor therapy and chemotherapy.
These patients were aged a median 65 years and the majority were female (57%), White (85%), and current or former smokers (95%), with nonsquamous histology (96%) and an ECOG performance status of 1 (78%).
The participants were given adagrasib 600 mg twice daily during phase 1/1b of the study (n=18) or phase 2 (n=61) and followed up for a pooled median of 3.6 months, including a median 9.6 months for the phase 1/1b participants.
Treatment-related adverse events (TRAEs) of any grade were reported for 85% of the 110 patients given this dosage, including 31 patients from other study cohorts, but just 4.5% of patients discontinued adagrasib as a result.
The most common TRAEs were gastrointestinal symptoms, such as nausea (54%), diarrhea (51%), and vomiting (35%), as well as fatigue (32%) and elevated alanine and aspartate transaminase (17–20%), with grade 3–4 events reported for 30% of patients, including fatigue (6%), both liver enzymes (5% each), and QT prolongation (3%).
There were two fatal TRAEs; one case of recurrent pneumonitis and one case of heart failure, the investigator added.
Riely reported biomarker analysis findings for three patients who underwent biopsy before and after 8 days of adagrasib treatment, describing “clear evidence” of signaling disruption of both KRAS and downstream pathways.
In addition, 51 patients underwent assessment for an objective response, with a partial response detected in 45% and stable disease in 51%, translating to a 96% disease control rate.
The median duration of response for 14 patients in the phase 1/1b group was 8.2 months, with four of six responders in this group continuing with adagrasib therapy after more than 11 months of treatment.
Riely et al also investigated the impact of co-mutations on adagrasib efficacy in the study, finding that 64% of patients who had an STK11 mutation achieved a partial response to treatment versus just 33% of those without this alteration. By contrast, the presence of KEAP1 or TP53 co-mutations did not appear to be linked to response rates, he said.
Three patients with STK11 co-mutations were classified as having “cold” tumors at baseline due to the absence of immune transcripts but two of these patients subsequently showed an increase in immune transcripts after adagrasib therapy.
Postulating that adagrasib therapy might allow T cell recruitment to the tumor, and potentially reverse STK11-mediated immune suppression, the presenter reported that patients with KRAS and STK11 co-mutations are now being recruited for a new cohort in the ongoing KRYSTAL-1 trial.
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